Hyperpolarized gas containers, solenoids, transport and storage devices and associated transport and storage methods

ABSTRACT

A compact portable transport unit for shipping hyperpolarized noble gases and shielding same from electromagnetic interference and/or external magnetic fields includes a means for shifting the resonance frequency of the hyperpolarized gas outside the bandwidth of typical frequencies associated with prevalent time-dependent fields produced by electrical sources. Preferably the transport unit includes a magnetic holding field which is generated from a solenoid in the transport unit. The solenoid includes a plurality of coil segments and is sized and configured to receive the gas chamber of a container. The gas container is configured with a valve, a spherical body, and an extending capillary stem between the valve and the body. The gas container or hyperpolarized product container can also be formed as a resilient bag. The distribution method includes positioning a multi-bolus container within the transport unit to shield it and transporting same to a second site remote from the first site and subsequently dispensing into smaller patient sized formulations which can be transported (shielded) in another transport unit to yet another site.

RELATED APPLICATIONS

This application claims the benefit of priority from ProvisionalApplication No. 60/089,692, filed Jun. 17, 1998, entitled “Containersfor Hyperpolarized Gases and Associated Methods” and ProvisionalApplication No. 60/121,315, filed Feb. 23, 1999, entitled“Hyperpolarized Gas Containers, Solenoids, and Transport and StorageDevices and Associated Transport and Storage Methods.” The contents ofthese applications are hereby incorporated by reference as if recited infull herein.

This invention was made with Government support under National Instituteof Health Grant No. R43HL62756-01 and Grant No. 7R44HL59022-03. TheUnited States Government has certain rights in this invention.

FIELD OF THE INVENTION

The present invention relates generally to the transport ofhyperpolarized gases from one site to another, such as from a productionsite to a clinical use site. The hyperpolarized gases are particularlysuitable for MR imaging and spectroscopy applications.

BACKGROUND OF THE INVENTION

Inert gas imaging (“IGI”) using hyperpolarized noble gases is apromising recent advance in Magnetic Resonance Imaging (MRI) and MRspectroscopy technologies. Conventionally, MRI has been used to produceimages by exciting the nuclei of hydrogen molecules (present in waterprotons) in the human body. However, it has recently been discoveredthat polarized noble gases can produce improved images of certain areasand regions of the body which have heretofore produced less thansatisfactory images in this modality. Polarized Helium-3 (“³He”) andXenon-129 (“¹²⁹Xe”) have been found to be particularly suited for thispurpose. Unfortunately, as will be discussed further below, thepolarized state of the gases is sensitive to handling and environmentalconditions and can, undesirably, decay from the polarized staterelatively quickly.

Various methods may be used to artificially enhance the polarization ofcertain noble gas nuclei (such as ¹²⁹Xe or ³He) over the natural orequilibrium levels, i.e., the Boltzmann polarization. Such an increaseis desirable because it enhances and increases the MRI signal intensity,allowing physicians to obtain better images of the substance in thebody. See U. S. Pat. No. 5,545,396 to Albert et al., the disclosure ofwhich is hereby incorporated by reference as if recited in full herein.

A “T₁” decay time constant associated with the longitudinal relaxationof the hyperpolarized gas is often used to characterize the length oftime it takes a gas sample to depolarize in a given situation. Thehandling of the hyperpolarized gas is critical because of thesensitivity of the hyperpolarized state to environmental and handlingfactors and thus the potential for undesirable decay of the gas from itshyperpolarized state prior to the planned end use, e.g., delivery to apatient for imaging. Processing, transporting, and storing thehyperpolarized gases—as well as delivering the gas to the patient or enduser—can expose the hyperpolarized gases to various relaxationmechanisms such as magnetic field gradients, surface-induced relaxation,hyperpolarized gas atom interactions with other nuclei, paramagneticimpurities, and the like.

One way of minimizing the surface-induced decay of the hyperpolarizedstate is presented in U.S. Pat. No. 5,612,103 to Driehuys et al.entitled “Coatings for Production of Hyperpolarized Noble Gases.”Generally stated, this patent describes the use of a modified polymer asa surface coating on physical systems (such as a Pyrex™ container) whichcontact the hyperpolarized gas to inhibit the decaying effect of thesurface of the collection chamber or storage unit. Other methods forminimizing surface or contact-induced decay are described in co-pendingand co-assigned U.S. patent application Ser. No. 09/163,721 to Zollingeret al., entitled “Hyperpolarized Noble Gas Extraction Methods, MaskingMethods, and Associated Transport Containers,” and co-pending andco-assigned U.S. Patent Application identified by Attorney Docket No.5770-12IP, entitled “Resilient Containers for Hyperpolarized Gases andAssociated Methods.” The contents of these applications are herebyincorporated by reference as if recited in full herein.

However, other relaxation mechanisms arise during production, handling,storage, and transport of the hyperpolarized gas. These problems can beparticularly troublesome when storing the gases (especially increasedquantities) or transporting the hyperpolarized gas from a productionsite to a (remote) use site. In transit, the hyperpolarized gas can beexposed to many potentially depolarizing influences. In the past, afrozen amount of hyperpolarized ¹²⁹Xe (about 300 cc-500 cc's) wascollected in a cold finger and positioned in a metallic coated dewaralong with a small yoke of permanent magnets arranged to provide amagnetic holding field therefor. The frozen gas was then taken to anexperimental laboratory for delivery to an animal subject.Unfortunately, the permanent magnet yoke provided a relatively smallmagnetic field region (volume) with a relatively low magnetichomogeneity associated therewith. Further, the thawed sample yielded arelatively small amount of useful hyperpolarized ¹²⁹Xe (used for smallanimal subjects) which would not generally be sufficient for most humansized patients.

There is, therefore, a need to provide improved ways to transporthyperpolarized gases so that the hyperpolarized gas is not undulyexposed to depolarizing effects during transport. Improved storage andtransport methods and systems are desired so that the hyperpolarizedproduct can retain sufficient polarization and larger amounts to alloweffective imaging at delivery when stored or transported over longertransport distances in various (potentially depolarizing) environmentalconditions, and for longer time periods from the initial polarizationthan has been viable previously.

OBJECTS AND SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide atransport system that can protect hyperpolarized gas products frompotentially depolarizing environmental exposures during movement of thehyperpolarized gas products from a production site to a remote use site.

It is also an object of the present invention to configure a transportunit to serve alternatively or in addition as a portable storage unit,to hold polarized gases in their polarized state for longer periodsincluding prior to shipment, or prior to delivery even if the gases arenot intended to be remotely shipped.

It is also an object of the present invention to provide a portable unitfor storing or transporting a quantity of hyperpolarized gas therein,which can substantially protect the hyperpolarized gas from thedepolarizing effect of diffusion of the gas atoms through magnetic fieldgradients.

It is another object of the present invention to provide a portable unitfor storing or transporting a quantity of hyperpolarized gas therein,which can substantially protect the hyperpolarized gas from thedepolarizing effects of one or more of oscillating magnetic fields,electromagnetic noise, and electromagnetic interference (EMI).

It is another object of the present invention to provide a method ofprotecting the hyperpolarized gas from the depolarizing effects ofundesirable EMI at a predetermined frequency or frequency range.

It is another object of the invention to provide a relatively compact,lightweight, easily transportable device which can provide sufficientprotection for the hyperpolarized gas to allow the hyperpolarized gas tobe successfully transported (such as in a vehicle) from a productionsite to a remote use site, such that the hyperpolarized gas retains asufficient level of polarization at the use site to allow for clinicallyusefull images.

It is another object of the invention to provide a valved hyperpolarizedgas chamber configured to inhibit polarization decay (i.e., hasrelatively long decay times) during transport and/or storage.

It is another object of the invention to configure a transport unit tominimize the external force associated with shock, vibration, and orother mechanical collisions that are input into or transmitted to thehyperpolarized gas container.

It is another object of the invention to provide a protective enclosurefor a transport unit which is configured such that the hyperpolarizedgas held in an internally disposed hyperpolarized gas chamber may bedirected out of or into the transport unit (i.e., the gas chamber may befilled and/or emptied), without the need to remove the gas chamber fromits protective housing.

It is another object of the invention to configure a transport unit withan easily accessible means for interrogating the polarized gas heldwithin the gas chamber held therein using nuclear magnetic resonance(NMR), in order to measure the polarization of the gas, or to measurethe decay rate of the polarization.

It is another object of the invention to provide a means of adjustingthe magnetic field strength generated by a transport unit, in order toshift the Larmor frequency of the spins associated with thehyperpolarized gas, either for purposes of NMR measurements, or tominimize decay from electromagnetic interference at a frequency ofinterest.

It is an additional object of the present invention to increase theshielding effectiveness of transport units.

It is still another object of the invention to provide a way totransport hyperpolarized gases from a polarization site to a secondaryand/or tertiary distribution site while maintaining a sufficient levelof hyperpolarization to allow clinically useful images at the ultimateuse site.

These and other objects of the present invention are provided by thetransport (and/or storage) units of the instant invention which areconfigured to protect hyperpolarized gas (and gas products and in one ormultiple containers) held therein, thereby minimizing depolarizinglosses introduced during transport of a hyperpolarized gas product fromone place to another. In particular, a first aspect of the invention isdirected toward a transport unit used to transport hyperpolarizedproducts therein. The transport unit comprises at least one gas chamberconfigured to hold a quantity of hyperpolarized product therein and atleast one electromagnet providing a magnetic holding field defining atleast one region of homogeneity. The homogeneous region of the magneticholding field is sized and configured to receive a major portion of thegas chamber (gas holding container) therein. The magnetic holding fieldis preferably primarily provided by a solenoid comprising at least onecurrent carrying wire thereon. In one embodiment, the gas chamber isdefined by a rigid body single or multi-dose container. In analternative embodiment, the gas chamber is defined by a resilient bodycontainer with an expandable gas chamber (preferably sized andconfigured to hold a single patient dose).

In one preferred embodiment, a solenoid coil is configured to generatethe magnetic holding field. Preferably the solenoid coil is also sizedand configured to maximize the volume of the sufficiently homogeneousregion provided thereby. Also preferably, the transport unit preferablyincludes one or more layers of an electrically conducting metal aboutthe enclosure. As such, the enclosure can provide shielding fromexternal electromagnetic radiation as well as mechanical support andprotection. The transport unit may also include one or more layers ofmagnetically permeable materials, such as soft iron or mu-metal, toprovide additional electromagnetic shielding, (including DC magneticshielding), or to act as a flux return.

A further aspect of the present invention is a solenoid coil forproviding a homogeneous magnetic field region in which thehyperpolarized gas is held. The solenoid comprises a cylindrical bodyand a first coil segment having a first coil length and a first numberof windings disposed on the cylindrical body. The solenoid also includessecond and third coil segments having respective second and third coillengths and respective second and third number of windings disposed onthe cylindrical body. The first, second, and third coil segments arespatially separated and positioned on the cylindrical body such that thesecond coil segment is intermediate the first and third coil segments.In a preferred embodiment, the second coil length is greater than bothof the first and third coil lengths and the first and third windings areconfigured with a greater number of layers relative to the secondwinding. This coil configuration can advantageously provide a largersufficiently homogeneous holding region for the hyperpolarized gaswithin a relatively compact coil area, thereby allowing the coil (aswell as any associated transport unit) itself to be more compact whilealso providing for a useful dose of the hyperpolarized gas to becontained and protected therein.

Another aspect of the present invention is a hyperpolarized gas productcontainer having a gas holding chamber and a capillary stem. Thecapillary stem has an inner diameter and length configured and sizedsuch that the capillary stem preferably inhibits the migration ordiffusional exchange of the hyperpolarized gas product between the mainbody of the chamber and the upper portion of the gas container whichpreferably includes a valve. More specifically, the capillary stem issized such that the ratio of the main body volume to the volume in thecapillary stem, multiplied by the diffusion time for ³He to traverse thelength of the capillary, is greater than the T₁ of a sealed chamber ofthe same material and dimensions. Exchange of gas product between themain body and the valve is undesirable because the valve is typically ina region of higher magnetic field gradients. Further, the valve maycomprise materials that can undesirably introduce surface-inducedrelaxation into the polarized gas. The container itself may beconfigured as a rigid body or resilient body.

Yet another aspect of the present invention is a transport unitincluding at least one resilient container (and preferably a pluralityof resilient containers) for holding a quantity of hyperpolarized gas(or liquid) product therein. In operation, one or more of the resilientcontainers are positionable within a homogeneous region of a magneticfield produced by the transport and/or storage unit.

Another aspect of the present invention is a system for distributinghyperpolarized gases, and preferably patient sized doses ofhyperpolarized gases. The system includes a first transport unit whichis sized and configured to hold a large multi-dose container therein.The system also includes at least one second transport unit sized andconfigured to carry a plurality of single dose containers therein.Preferably, the multi-dose container is a rigid body container and thesingle dose containers are resilient containers having expandablechambers to allow easy delivery or administration at a use site.

Similarly, in one embodiment, the multi-dose container is transported toa pharmaceutical distribution point where the hyperpolarized gas in themulti-dose container can be formulated into the proper dosage or mixtureaccording to standard pharmaceutical industry operation. This mayinclude solubilizing the gas, adjusting the concentration, preparing themixture for injection or inhalation or other administration as specifiedby a physician, or combining two different gases or liquids or othersubstances with the transported hyperpolarized gas. Then, the formulatedhyperpolarized product, substance, or mixture is preferably dispensedinto at least one second container, and preferably into a plurality ofpreferably a single use size resilient containers which can betransported to a third or tertiary site for use. In a preferredembodiment, the first transport distance is such that the hyperpolarizedgas is moved at increased times or distances over conventional uses.Preferably, the transport units and associated container of the presentinvention are configured such that during transport and/or storage, thehyperpolarized gas (particularly ³He) retains sufficient polarizationafter about 10 hours from polarization, and preferably after at least 14hours, and still more preferably (especially for ³He) after about 30hours. Stated differently, the transport units and associated containersof the instant invention allow clinical use after about 30 hours elapsedtime from original polarization and after transport to a second site(and even then a third or tertiary site). The transporters andcontainers are also preferably configured to allow greater transitdistances or greater transit times. Stated differently, thehyperpolarized product retains sufficient polarization after transportand greater elapsed time from polarization when positioned in thetransport units to provide clinically useful images. This distributionsystem is in contrast to the conventional procedure, whereby thehyperpolarized gas is produced at a polarization site and rushed to ause site (which is typically relatively close to the polarization site).

An additional aspect of the present invention is directed toward amethod of minimizing the relaxation rate of hyperpolarized noble gasesdue to external electromagnetic interference. The method includes thesteps of capturing a quantity of hyperpolarized gas in a transportablecontainer and shifting the resonant frequency of the hyperpolarizednoble gas out of the frequency range of predetermined electromagneticinterference. Preferably, the method includes shifting the normalresonance frequency associated with the hyperpolarized gas to afrequency substantially outside the bandwidth of prevalenttime-dependent fields produced by electrically powered equipment (suchas computer monitors), vehicular engines, acoustic vibrations, and othersources. In a preferred embodiment, the resonant frequency of thehyperpolarized gas is shifted by applying a static magnetic fieldproximate to the hyperpolarized gas. For example, preferably for ahyperpolarized gas product comprising ³He, the applied static magneticfield is at least about 7 Gauss, while for hyperpolarized gas productscomprising ¹²⁹Xe, the applied magnetic field is at least about 20 Gauss.

Yet another aspect of the present invention is directed toward a systemfor preserving the polarization of the gas during transport. The systemincludes the steps of introducing a quantity of hyperpolarized gasproduct into a sealable container comprising a gas chamber at aproduction site and capturing a quantity of hyperpolarized gas productin the gas chamber. A magnetic holding field is generated by a portabletransport unit defining a substantially homogeneous magnetic holdingregion therein. The gas chamber is positioned within the homogeneousholding region and the hyperpolarized gas product is shielded tominimize the depolarizing effects of external magnetic fields such thatthe hyperpolarized gas has a clinically useful polarization level at asite remote from the production site.

In a preferred embodiment, the step of providing the magnetic holdingfield is performed by electrically activating a longitudinally-extendingsolenoid positioned in the transport unit. The solenoid comprises aplurality of spatially separated coil segments, and the sealablecontainer comprises a capillary stem in fluid communication with the gaschamber.

The present invention is advantageous because the transport unit canprotect the hyperpolarized gas and minimize the depolarizing effectsattributed to external magnetic fields, especially deleteriousoscillating fields, which can easily dominate other relaxationmechanisms. The transport container is relatively compact and is, thus,easily portable. Preferably, the transport unit includes a homogeneousmagnetic holding field positioned proximate to the gas container so thatit provides adequate protection for the hyperpolarized state of the gasand facilitates the transport of the gas to an end use site. In apreferred embodiment, the transport unit includes a solenoid having atleast a three-coil segment configuration with the central coil segmenthaving a reduced number of wire layers compared to the other (opposing)two coil segments. Stated differently, the opposing end segments have agreater number of wire layers providing increased current density(current per unit length) in these areas. Advantageously, such a coilsegment design can enlarge the homogeneous region of the magnetic fieldgenerated by the solenoid while minimizing the size (length) of thesolenoid itself. This relatively compact transport unit can easilydeliver a single patient dose or a plurality of patient doses (combinedor individual).

Further, the transport unit is configured such that it can use anadjustable current to allow field adjustments, thereby enablingcorrection for one or more of electronic or mechanical drift, the typeof gas transported, and severe exposure conditions. In addition, thetransport unit can be employed with more than one type of hyperpolarizedgas, for example, ³He or ¹²⁹Xe. In addition, the transport unit can beconfigured such that the hyperpolarized gas can be released at the enduse site without removing the typically somewhat fragile gas chamberfrom the transport unit (when glass chambers are employed). Thiscapability can protect the gas from intermediate depolarizing handlingand can also facilitate the safe release of the gas by shielding anyusers proximate to the transport unit from exposure to the internal gascontainer (such as a glass sphere) which is typically under relativelyhigh pressure. Alternatively, the transport unit can shield resilientlyconfigured gas containers to provide easy to dispense single dose sizedproducts. In addition, the gas container preferably includes a capillarystem and/or a port isolation means which inhibits the diffusion ormovement of the hyperpolarized gas out of the main body, thereby helpingto retain a majority of the hyperpolarized gas within the homogeneousholding region and inhibiting contact between the hyperpolarized gas andthe potentially depolarizing materials in the sealing means. Further,the enclosure walls of the instant invention are preferably configuredsuch that they provide adequate spatial separation from the gascontainer to increase the shielding effectiveness of the transport unit.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cutaway front perspective view of a transport unit accordingto the present invention, the transport unit comprising a gas chamberand solenoid.

FIG. 2 is an enlarged cutaway front view of the solenoid and gas chambershown in FIG. 1.

FIG. 2A is a perspective view of the solenoid shown in FIGS. 1 and 2.

FIG. 3 is a cutaway perspective view of the solenoid of FIG. 2Aillustrating the current direction and the magnetic holding fielddirection and the region of highest homogeneity in the solenoid.

FIG. 3A is a graph that illustrates a preferred winding/currentdistribution relative to the distance along the length of the solenoid,with (2i) representing a current density which is twice that of thecenter coil segment (i), along with points of negligible current betweenthe coil segments.

FIG. 4 is a side view of a gas chamber configuration particularlysuitable for use with the transport unit according to the presentinvention.

FIG. 5 is a front perspective view of the transport unit shown in FIG.1.

FIGS. 6, 6A, and 6B are perspective views of transport units configuredto transport multiple containers of hyperpolarized gas productsaccording to alternate embodiments of the present invention.

FIG. 7 is a schematic illustration of a power monitoring and switchingcircuit for use with a portable transport unit according to the presentinvention.

FIG. 8 is a schematic illustration of an operating circuit for use witha portable transport unit associated with a preferred embodiment of thepresent invention.

FIG. 9 is a front perspective view of a calibration/docking stationaccording to the present invention.

FIG. 10 is a graphical representation of the normalized magnetic fieldgenerated by an embodiment of the solenoid of the instant invention (topbell-shaped curve) compared to a coil having uniform current density perunit length (bottom bellshape curve).

FIG. 11 is a flow chart of a system for shielding hyperpolarized gasfrom the depolarizing effects attributed to external magnetic fieldsduring transport, thereby preserving the polarized life of the gas.

FIG. 12A is a perspective partial cutaway view of a multi-transportdistribution system. The distribution system delivers a multi-dosecontainer to a second site remote from the polarization site. At thesecond site, the hyperpolarized product in the multi-dose container isdivided, mixed, or otherwise formulated into resilient single usecontainers for delivery to a teritary (preferably clinical use site)according to the present invention.

FIG. 12B is an exploded view of a tray for facilitating positioning of aplurality of single-sized resilient containers in a single solenoidsized to accommodate same.

FIG. 13 is a perspective partial cutaway view of a distribution systemwhich employs a plurality of magnetic holding field generators in thesecond transport unit.

FIG. 14 is a flow chart of a distribution system according to thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more fully hereinafter withreference to the accompanying drawings, in which preferred embodimentsof the invention are shown. This invention may, however, be embodied inmany different forms and should not be construed as limited to theembodiments set forth herein; rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the invention to those skilled in the art. Likenumbers refer to like elements throughout. In the figures, layers andregions may be exaggerated for clarity.

For ease of discussion, the term “hyperpolarized gas” is used todescribe a hyperpolarized gas alone, or a hyperpolarized gas thatcontacts or combines with one or more other components, whether gaseous,liquid, or solid. Thus, the hyperpolarized gas described herein can be ahyperpolarized gas composition/mixture (preferably non-toxic such thatit is suitable for in vivo administration) such that the hyperpolarizedgas can be combined with other gases and/or other inert or activesubstance or components. Also, as used herein, the term “hyperpolarizedgas” can include a product in which the hyperpolarized gas is dissolvedinto another liquid (such as a carrier fluid) or processed such that ittransforms into a substantially liquid state, i.e., “a liquid polarizedgas”. In summary, as used herein, the term “gas” has been used incertain places to descriptively indicate a noble gas which has beenhyperpolarized and which can include one or more components and whichmay be present in or further processed to be in one or more physicalforms.

Background-Hyperpolarization

Various techniques have been employed to polarize, accumulate andcapture polarized gases. For example, U.S. Pat. No. 5,642,625 to Cateset al. describes a high volume hyperpolarizer for spin-polarized noblegas and U.S. Pat. No. 5,642,625 to Cates et al. describes a cryogenicaccumulator for spin-polarized ¹²⁹Xe. The disclosures of this patent andapplication are hereby incorporated herein by reference as if recited infull herein. As used herein, the terms “hyperpolarize” and “polarize”are used interchangeably and mean to artificially enhance thepolarization of certain noble gas nuclei over the natural or equilibriumlevels. Such an increase is desirable because it allows stronger imagingsignals corresponding to better MRI images of the substance in atargeted area of the body. As is known by those of skill in the art,hyperpolarization can be induced by spin-exchange with an opticallypumped alkali-metal vapor or alternatively by metastability exchange.See U.S. Pat. No. 5,545,396 to Albert et al. The alkali metals capableof acting as spin exchange partners in optically pumped systems includeany of the alkali metals. Preferred alkali metals for thishyperpolarization technique include Sodium-23, Potassium-39,Rubidium-85, Rubidium-87, and Cesium-133.

Alternatively, the noble gas may be hyperpolarized using metastabilityexchange. (See e.g., Schearer, L. D., Phys Rev, 180:83 (1969); Laloe,F., Nacher, P. J., Leduc, M., and Schearer L. D., AIP ConfProx #131(Workshop on Polarized ³He Beams and Targets) (1984)). The technique ofmetastability exchange involves direct optical pumping of, for example,³He without the need for an alkali metal intermediary. Since thisprocess works best at low pressures (0-10 Torr), a compressor istypically used to compress the ³He after the hyperpolarization step.

Regardless of the hyperpolarization method used, once the activemechanism is no longer in effect, the polarization of the gas willinevitably decay toward its thermal equilibrium value, which isessentially zero. The present invention is configured to work with anyhyperpolarization technique and, as will be appreciated by one of skillin the art, is not limited to working with any one type of machine,method, or particular gas.

Polarized Gas Relaxation Processes

Under most circumstances, the non-equilibrium polarization P(t) of a gasdecays according to

dP(t)/dt=−P(t)/T₁  1.0

The overall decay rate is equal to the sum of rates from variousmechanisms:

1/T₁=(1/T₁)_(Gas)+(1/T₁)_(Surface)+(1/T₁)_(EMI)+(1/T₁)_(Gradient)  2.0

Gas Interaction Relaxation

The first decay term (1/T₁)_(Gas) represents the depolarization of thenoble gas nuclei when interacting with each other and can also includeinteraction of the atoms with gaseous impurities such as oxygen. Thus,carefull preparation of gas containment, transfer, and extractionsystems is important for providing good polarization lifetimes as willbe discussed further below. Examples of suitable gas extraction methodsand apparatus are described in co-pending and co-assigned U.S. patentapplication Ser. No. 09/163,721, entitled “Hyperpolarized Noble GasExtraction Methods, Masking Methods, and Associated TransportContainers,” identified by Attorney Docket No. 5770-14, the disclosureof which is hereby incorporated by reference as if recited in fullherein.

Even in the absence of all other relaxation mechanisms, collisionsbetween identical polarized gas atoms impose a fundamental upper limitto the achievable T₁ lifetime. For example, ³He atoms relax through adipole-dipole interaction during ³He—³He collisions, while ¹²⁹Xe atomsrelax through N·I spin rotation interaction (where N is the molecularangular momentum and I designates nuclear spin rotation) during¹²⁹Xe—¹²⁹Xe collisions. In any event, because both processes occurduring noble gas-noble gas collisions, both resulting relaxation ratesare directly proportional to number density (T₁ is inverselyproportional to number density). At one bar pressure, the theoreticalmaximum relaxation time T₁ of ³He is about 750 hours, and for ¹²⁹Xe thecorresponding relaxation time is about 56 hours. See Newbury et al.,“Gaseous 3He—3He Magnetic Dipolar Spin Relaxation,” 48 Phys. Rev. A.,No. 6, p. 4411 (1993); Hunt et al., “Nuclear Magnetic Resonance of ¹²⁹Xein Natural Xenon,” 130 Phys Rev. p. 2302 (1963).

Unfortunately, other relaxation processes such as surface relaxation,electromagnetic interference (EMI), and magnetic gradient relaxation canprevent the realization of these theoretical relaxation times.Accordingly, each of these mechanisms are of concern when handlinghyperpolarized gases and are preferably addressed so as to allow for theoverall relaxation time to be sufficiently large.

Surface-induced Relaxation

The (1/T₁)_(surface) term represents the surface-induced relaxationmechanism. For example, the collisions of gaseous ¹²⁹Xe and ³He withcontainer walls (“surface relaxation”) have historically been thought todominate most relaxation processes. For ³He, most of the known longerrelaxation times have been achieved in special glass containers having alow permeability to helium. See Fitzsimmons et al., “Nature of surfaceinduced spin relaxation of gaseous He-3,” 179 Phys. Rev., No. 1, p. 156(1969). U.S. Pat. No. 5,612,103 to Driehuys et al. describes usingcoatings to inhibit the surface-induced nuclear spin relaxation ofhyperpolarized noble gases, especially ¹²⁹Xe. The contents of thispatent are hereby incorporated by reference as if recited in fullherein. Similarly, co-pending and co-assigned U.S. patent applicationSer. No. 09/126,448 to Deaton et al., and its related applicationidentified by Attorney Docket No. 5770-12IP, describe preferredgas-contact surface materials and associated thicknesses, O-rings, andvalve or seal materials and/or coatings which are friendly to thepolarized state of the gas, i.e., which can inhibitsurface/contact-induced relaxation mechanisms. The content of theseapplications are also hereby incorporated by reference as if recited infull herein.

Electromagnetic Interference

The relaxation mechanism expressed by the term (1/T₁)_(EMI) is therelaxation induced by time-dependent electromagnetic fields. Indeed, EMIcan potentially destroy the hyperpolarized state of the gas (EMI isparticularly problematic if coherent at the magnetic resonancefrequency). Unfortunately, EMI can be generated by relatively commonsources. For example, EMI is typically generated from a vehicle'sengine, high voltage lines, power stations and other current carryingentities. As such, transport away from the hyperpolarized gas productionsite can expose the hyperpolarized gas to these undesirable relaxationsources that, in turn, can dramatically reduce the polarization lifetimeof the transported gas.

Fluctuating fields are particularly deleterious if they are coherent atthe magnetic resonance frequency. For example, assuming a generallyworst case scenario of a highly coherent oscillating field, it isexpected that the relaxation rate is comparable to the Rabi frequency:

(1/T₁)_(EMI)≈γH_(AC)/2  2.10

Here, “γ” is the gyromagnetic ratio of the spins, and “H_(AC)” is themagnitude of the transverse fluctuating field. A resonant field H_(AC)of only 1 μG would cause relaxation on a time scale of order 100 secondsfor ³He. On the other hand, if the field is randomly fluctuating, therelaxation rate is given by

(1/T₁)_(EMI)=γ²<H_(AC) ²>τ_(c)/(1+ω²τ_(c) ²)  2.20

where “τ_(c)” is the autocorrelation time of the fluctuations, “ω” isthe Larmor frequency of the spins, and “<H_(AC) ²>” is the mean value ofthe square of the fluctuating transverse field component. In the randomfluctuation case, the rate can be suppressed by increasing ω, (which isproportional to the holding field strength), particularly if ωτ_(c)>1.In either case, the relaxation rate can be suppressed by reducing themagnitude of the interference H_(AC).

Magnetic Field Gradients

Magnetic gradient relaxation expressed by the term (1/T₁)_(Gradient) isassociated with the relaxation attributed to the exposure of thehyperpolarized noble gases to inhomogeneous static magnetic fields.Generally stated, as the polarized gas atoms diffuse or move through aninhomogeneous magnetic field, they experience a time-dependent field,which can introduce depolarizing activity onto the hyperpolarized atoms.For example, at typical pressures (i e., about 1 bar), the relaxationrate attributed to a static magnetic field gradient can be expressed bythe following equation:

(1/T₁)_(Gradient)=D(|∇B_(x)|²+|∇B_(y)|²)/B_(z) ²  2.30

Here, “B_(z)” is the primary component of the static magnetic field,“∇B_(x)” and “∇B_(y)” represent the gradients of the transverse fieldcomponents, and “D” is the diffusion coefficient of the polarized atomsthrough the gas. For example, for pure ³He at 1 bar pressure, thediffusion coefficient D≈1.9 cm²/s. In the earth's magnetic field(generally represented by a static magnetic field of about 0.5 G), a 5mG/cm transverse field gradient causes a relaxation rate(1/T₁)_(Gradient) of about 1.9×10⁻⁴s⁻¹(i.e., a ³He T₁ of about 1.5hours). In contrast, in a 5 gauss field (as opposed to a 0.5 gaussfield), the same 5 mG/cm gradient will typically yield a T₁ of about 150hours. Thus a magnetic field homogeneity on the order of 10−3 cm-⁻¹ isdesirable to make gradient relaxation tolerable at these pressures.Alternatively, higher gradients are acceptable if the ³He is pressurizedto at least several bars of pressure, or alternatively mixed withanother gas such as nitrogen or argon to restrict diffusion, i.e., lowerthe diffusion coefficient. As will be appreciated by those of skill inthe art, during transport, it is desirable to avoid inhomogeneousmagnetic fields, e.g., to avoid nearby ferromagnetic objects. Forexample, it is desired to maximize to the extent possible the spatialdistance between the hyperpolarized gas and objects that can producestrong magnetic fields and/or magnetic field gradients.

Shielding

The present invention recognizes that unless special precautions aretaken, relaxation due to external magnetic fields (static and/or timedependent) can dominate all other relaxation mechanisms. As discussedabove, both gradients in the static field and (low frequency)oscillating magnetic fields experienced by the hyperpolarized gas cancause significant relaxation.

Advantageously, the instant invention employs an (externally) appliedsubstantially static magnetic holding field “B_(H)” to substantiallyprotect the hyperpolarized gas from depolarizing effects attributed toone or more of the EMI and gradient fields during transport. The instantinvention employs a magnetic holding field which raises the Larmorfrequency of the hyperpolarized gas above the region of noise (1/f),i.e., the region where the intensity of ambient electromagnetic noise istypically high (this noise is typically under about 5 kHz). Further, themagnetic holding field of the instant invention is also preferablyselected such that it raises the frequency of the hyperpolarized gas toa level which is above those frequencies associated with large acousticvibrations (these acoustic vibrations are typically less than about 20kHz). As will be discussed below, the increased frequency associatedwith the applied magnetic holding field advantageously allows atransport unit to have greater electromagnetic shielding effectivenessfor a given housing thickness (the housing used to hold thehyperpolarized gas therein during transport). The skin depth “δ” of aconductive shielding material is inversely proportional to the squareroot of the frequency. Thus, at 25 kHz, an exemplary skin depth foraluminum is about 0.5 mm, as compared to about 2.0 mm at 1.6 kHz.

Preferably, the magnitude of the magnetic holding field of the instantinvention is selected so that any external field-related fluctuationsare small in magnitude compared to the field strength of the holdingfield; in this way the holding field can minimize the hyperpolarizedgas's response to unpredictable external static field gradient-inducedrelaxation. This can be accomplished by applying to the hyperpolarizedgas a proximately positioned magnetic holding field which issufficiently strong and homogeneous so that it minimizes theunpredictable static field-related relaxation during transport. Asufficiently homogeneous holding field preferably includes (but is notlimited to) a magnetic holding field which has homogeneity which is onthe order of about at least 10⁻³ cm⁻¹ over the central part of theholding field. In the previous example, if a homogeneous field of about10 G were applied, the same 5 mG cm⁻¹ gradient would instead result inT₁≈600 hr. More preferably, the magnetic holding field homogeneity isabout at least 5×10⁻⁴ cm⁻¹ over about a region of interest (i.e., theregion of interest is region associated with the major volume of thehyperpolarized gas in the container(s)) in the transport unit.Preferably this volume is sized and configured as a volume in spacerepresenting about at least a three-inch diameter sphere. Further, thetransport unit 10 of the instant invention includes and provides amagnetic holding field which is positioned, sized, and configuredrelative to the hyperpolarized gas held therein such that it alsominimizes the EMI or oscillating magnetic field depolarization effectson same. The depolarizing effect of EMI is preferably (substantially)blocked by applying the magnetic holding field (B_(H)) proximate to thegas so that the resonant frequency of the hyperpolarized gas is adjustedto a predetermined frequency. Preferably, the predetermined frequency isselected such that it is above or outside the bandwidth of prevalenttime-dependent fields produced by electrically powered or suppliedsources.

Alternatively, or additionally, the external interference can beshielded by positioning a substantially continuous shield or shippingcontainer having at least one layer formed of a conductive material,such as metal, around the hyperpolarized gas in the container. Thepreferred shielding thickness is related to the spatial decay constantof an electromagnetic wave or skin depth “δ”. The skin depth δ at anangular frequency “ω”, given by “δ=c/(2πμσω)^(½)”, where “μ” is themagnetic permeability and “σ” is the electrical conductivity of thematerial. At these frequencies, the Larmor radiation wavelength isrelatively long (˜10 km), and is much larger than the container size.The shielding effectiveness is therefore dependent upon the containergeometry as well as the shielding thickness. For a thin sphericalconductor of radius “a” and thickness “t”, the shielding factor forwavelengths “λ” where λ>>a can be approximately represented by thefollowing equation

F=(1+(2at/3δ²)²)^(½)  2.4

Interestingly, the shielding effectiveness increases as the size(radius) of the shield is increased. It is therefore preferred that themetallic enclosure used to shield or surround the hyperpolarized gas beconfigured and sized to define an internal volume and spatial separationrelative to the gas which is sufficient to provide increased shieldingeffectiveness. Stated differently, it is preferred that the opposingwalls of the enclosure are spaced apart a predetermined distancerelative to the position of the gas container held therein. Preferably,the walls define a minimum linear separation for the major volume of thecontainer or chamber (the portion holding a major portion of thehyperpolarized gas or product) such that there is about at least 1.5inches, and more preferably at least about 2.0 inches, and even morepreferably at least about 2.5 inches of distance between the metallicwall and the leading edge of the gas holding chamber on all sides.

As shown in FIG. 1, the transport unit 10 has an enclosure 60 with ageometry in which the walls of the enclosure are configured and sized toprovide an internal volume 65 or geometry which is relatively large incomparison to the size of the gas container(s) 30 (30 b, FIG. 12). As isalso shown, the walls 63A, 63B, 63C, 63D are configured such that thegas holding chamber 30, when in position in the enclosure 60, is spacedapart a distance from the adjacent wall segments to provide sufficientspacing to facilitate the shielding effectiveness of the metallic wall.That is, the opposing walls 63B, 63C and 63A, 63D (and preferablyincluding the opposing top and bottom walls 63E, 60A) each have aminimum separation distance of preferably at least about 1.5 inches, andmore preferably at least 2.0 inches, and still more preferably at leastabout 2.5 inches in all directions from the major portion of the gasholding chamber 30. In a preferred configuration, the separationdistances of the container 30 (30 b, FIG. 12) as held in the transportunit 10, is sized and geometrically configured to define a maximumseparation ratio. That is, the separation ratio can be described as thelinear distance from the center of the major volume of the containerholding a volume of hyperpolarized gas to the edge thereof (i.e., thelinear half width, or the radius of a spherical gas chamber) to theminimum linear separation distance of each (or the closest) wall fromthe leading edge of the portion of the gas holding chamber holding themajor volume of the gas. Preferably, the container and enclosure areconfigured to provide a ratio which is less than about 0.60.

Alternatively, or additionally, the transport unit 10 can be configuredwith at least one layer formed from about 0.5 mm thick of magneticallypermeable material, such as ultra low carbon steel soft iron, ormu-metals (by virtue of their greater magnetic permeability). However,these materials may significantly influence the static magnetic fieldand must be designed accordingly not to affect the homogeneityadversely.

Irrespective of the skin depth of the materials (types of materials andnumber of layers) used to form the shipping container enclosure,application of a homogeneous magnetic holding field proximate to thehyperpolarized gas can help minimize the gas depolarization by virtue ofdecreasing the skin depth δ, which is inversely proportional to thesquare root of the frequency. Further, it helps by pushing the resonantfrequency of the gas outside the bandwidth of common AC fields. It ispreferred that the resonant frequency of the hyperpolarized gas beraised such that it is above about 10 kHz, and more preferably be raisedsuch that it is between about 20-30 kHz. Stated differently, it ispreferred that for shielding, the applied magnetic holding field have afield strength of about 2 to 35 gauss. It is more preferred that for¹²⁹Xe, the magnetic holding field is preferably at least about 20 Gauss;and for ³He, the magnetic holding field is preferably at least about 7Gauss.

Transport Unit

Referring now to FIG. 1, a transport unit 10 is illustrated according toa preferred embodiment of the instant invention. As shown, the transportunit 10 includes a magnetic field generator 20′ disposed therein, whichprovides a magnetic holding field (B_(H)) for the gas. As shown, themagnetic field generator is a solenoid 20, which is configured and sizedto receive a hyperpolarized gas storage chamber 30 therein. Thetransport unit 10 also includes a power source 40 and operatingcircuitry 50 preferably provided on an internally disposed printedcircuit board 51. The transport unit 10 preferably includes asubstantially non-ferromagnetic metallic case or housing enclosure 60having a predetermined skin depth appropriately sized to provide desiredshielding, and which includes a bottom portion 60B and a top 61A (FIG.5) that open to facilitate easy access to the exit port 31 and valve 32of the gas chamber 30. It is preferred that the transport unit 10 beconfigured with a minimal amount of ferromagnetic materials on or insidethe transport unit 10 (i.e., is substantially free of ferromagneticmaterials that are not intended for creating the homogeneous holdingfield). Although for ease of discussion, the term “transport” is used todescribe the unit, it will be appreciated by one of skill in the art,that the instant invention may also be used to store a quantity ofhyperpolarized gas product therein. As such, the term “transport unit”includes a unit that can be used as either a storage unit, a transportunit, or both a storage and transport unit.

As shown in FIGS. 1 and 5, the top 61A of the housing is hinged to thebottom of the case 60B, which defines an enclosure volume 65.Preferably, as shown in FIG. 1, the enclosure volume 65 is defined by acontiguous arrangement of four upstanding sidewalls 63A-63D (63D notshown) connected by a bottom wall 63E and a top face-plate 60A, 60A′.Thus, the enclosure 65 surrounds the gas chamber 30 and other internallymounted components (such as a power source 40 and operating circuitry50).

As shown in FIG. 5, the top portion 61A preferably includes latches200A, 200B which engage with corresponding components 210A, 210Bpositioned on the outside wall of the bottom portion of the case 60B tosecure the top 61A to the bottom to the bottom 60B when the top 61A isclosed (i.e., preferably during transport). Preferably, the enclosure 60and, indeed, the entire transport unit 10, is configured to bepolarization-friendly (substantially devoid of paramagnetic andferromagnetic materials) such that the transport unit 10 does notintroduce significant reductions in the polarization level of thehyperpolarized gas therein.

Generally stated, as electromagnetic leakage is proportional to holes oropenings in the housing 60, it is preferred, either when the top of thehousing 61A is closed or by configuring the face plate 60A to attach tothe bottom of the case 60B such that the exterior walls of the housing60 define a substantially continuous body (without openings) to minimizethe entry of electromagnetic waves inside the housing 60. Of course, thehousing 60 can include apertures as long as they are positioned orformed on the housing 60 such that any electromagnetic interferenceleakage is directed away from the solenoid core 33 where the gas chamber30 resides and/or are configured with a protective covering or seal toprovide sufficient housing integrity to minimize polarization lossattributed thereto. One suitable housing 60 is a relatively compactaluminum case (having about a 1 mm wall thickness) manufactured by ZeroEnclosures of Salt Lake City, Utah and was modified to substantiallyremove ferromagnetic hardware.

Preferably, the bottom of the case 60B and the face plate 60A and/or top61A includes at least one layer of an electrically conducting metalthereon, having a sufficient skin depth to thereby provide one or moreof shielding from external electromagnetic radiation, physicalprotection, and support of the gas container during transport.Alternatively, or additionally, the components of the housing 60 whichdefine the enclosure 65 (such as the walls and bottom 63A-63D, 63E andtop 61A) include at least one layer of magnetically permeable materialto provide either additional electromagnetic shielding, DC magneticshielding, and/or a flux return.

Preferably, as shown in FIG. 1, the transport unit 10 also comprises ametal face plate 60A, 60A′ positioned over the opening defined by theupper surface of the case when the top 61A is opened. As shown in FIGS.1 and 5, the face plate 60A, 60A′ is configured to substantially enclosethe side walls and bottom of the housing to provide an enclosure for thesolenoid 20 when the top 61A is open and yet also configured to allow auser access to a polarized gas chamber valve 32 and the hyperpolarizedgas exit port 31.

In a preferred embodiment, after delivery to a desired location, thevalve 32 is opened and the hyperpolarized gas is released from the gaschamber 30 through the exit port 31 while the gas chamber 30 itselfremains captured in the substantially enclosed housing 60. The bottomhousing 60 can add extra protection to personnel in the gas release areabecause the housing 60 surrounds a substantial portion of the gaschamber 30 therein, thereby providing a physical shield from anyunplanned release or untimely breakage of the chamber itself (typicallycomprising an alumnosilicate glass) and which is typically transportedunder pressure. Further details of the preferred gas chamber 30 will bediscussed below.

Solenoid

Turning to FIG. 2, it is preferred that the transport unit comprise anelectromagnet for providing the magnetic holding field. FIG. 2illustrates a preferred embodiment of the electromagnet configured as asolenoid 20 comprises a plurality of electrical coil segments forgenerating a substantially homogeneous static applied magnetic holdingfield (B_(H)). Of course, other electrical wire configurations (i.e.,electromagnetic arrangements) can also be used as will be appreciated byone of skill in the art. As will also be appreciated by one of skill inthe art, other magnetic field generators can also be employed such aspermanent magnets (so long as they provide sufficient homogeneity).Preferably, the solenoid 20 comprises at least three (3) electrical coilsegments 21, 22, 23 which are wrapped around an outer surface of thecylindrical wall of the solenoid body or core 20A. During fabrication,this outer surface placement of the coil segments 21, 22, 23 allows theouter wall of the solenoid core 20A to act as the wrapping spool. Thecylindrical spool can be formed of various preferably non-conductingmaterials such as polyvinyl chloride (PVC). Of course, the coil segments21, 22, 23 can be alternatively positioned on the cylindrical body. Forexample, the coil segments 21, 22, 23 can be wrapped onto anintermediate layer of a cylindrical body (or even an inner layer) aswill be appreciated by those of skill in the art.

As shown in FIGS. 1, 2 and 3, the solenoid 20 is oriented such that itextends longitudinally from the opposing top and bottom ends of thetransport unit 10. The coil segments 21, 22, 23 are circumferentiallywrapped around the respective portions of the cylindrical wall of thesolenoid core 20 a and are preferably configured such that the magneticholding field B_(H) (FIG. 3) is directed downward such that itpreferably aligns with the predominant direction of the earth's magneticfield (the field direction is generally indicated by element 100). Assuch, the current in the solenoid coil segments 21, 22, 23 is directedclockwise when viewing the solenoid from the top. This earthlydirectional alignment can maximize the magnitude of the holding fieldwith a given current.

As shown in FIGS. 2 and 2A, the first and third coil segments 21, 23 arepreferably positioned proximate to the top and bottom 20A, 20B of thesolenoid, respectively. The second coil segment 22 is positionedintermediate the first and third coil segments 21, 23. As shown, thesecond segment 22 is spatially separated by a separation distance 22A,22B from the first and third coil segments 21, 23.

FIG. 1 shows a preferred embodiment wherein substantially the entireinner diameter of the solenoid 20 is covered with a thin conductivematerial layer such as a metallic film or tape 24. FIGS. 1 and 2illustrate that the thin metallic layer 24 acts to provide a separatecolumnated electrical shield 24 a which extends between the top plate60A and the top surface of the bottom of the case 63E. As shown, theshield 24 a is formed as a thin metallic layer 24 which is arranged as aseries of wrapped and overlapping layers of aluminum foil tape whichextends from the top to the bottom of the solenoid 20. This thinmetallic layer 24 can also be provided by other metallic finishes, suchas by a metallic coating, metallic film or metallic elastomer and thelike.

Preferably the shield 24 a is configured such that at least the bottomend 24 b of the shield is in electrical contact with the case 60. In apreferred embodiment, the bottom end 24 b is configured to be inelectrical contact either directly or indirectly (i.e., via otherconductive components) with the case. In this embodiment, the bottom end24 b is configured such that the end defines a continuous electricalconnection around the entire bottom edge 24 b. Of course, othercomponents can be used to define an electrical bridge between the shield24 a and the case.

In another embodiment, both the top edge 24 c and the bottom edge 24 bof the shield 24 a are arranged to define a continuous electricalcontact with the respective adjacent portions of the case 60.

Further, in a preferred embodiment, as illustrated in FIG. 3A, the firstand third coil segments 21, 23 are configured with an increased numberof wire layers relative to the second coil segment 22. A preferredcurrent distribution is also illustrated in FIG. 3A. The increasednumber of layers associated with the first and third coil segments 21,23 relative to the second coil segment 22 acts to provide additionalcurrent density in these segments and to enlarge the homogeneous region,as shown in FIG. 3. FIG. 10 illustrates a broader “flatter” fieldstrength (Bz) which a solenoid having a plurality of winding segmentscan provide relative to a single winding configuration of the samelength having a uniform current density. FIG. 10 illustrates the singlewinding field as the bottom “bell-shaped” graph. As such, a solenoidwith a plurality of winding segments can increase the homogeneousholding region in the solenoid along a greater distance about the centerof the solenoid body (distance from “0” along the “z-position”).

As shown in FIG. 3A, the solenoid 20 is turned on its side (relative tothe transit position shown in FIG. 1) and a preferred currentdistribution relative to each coil segment 21, 22, 23 is graphicallyillustrated. The first and third coil segments 21, 23 correspond to afirst current density value (2i/l) and the intermediate or second coilsegment corresponds to a lesser current density value, preferably abouthalf the end current density value (i.e., about (i/l)). (There isnegligible current in the gaps 21A, 22A, 22B and 23A). As shown, it ispreferred that each of the first and third coil segments 21, 23 have acurrent density value which is substantially the same, while the secondcoil segment 22 has a current density value (i/l) which is about half ofthat of the first and third coil segments 21, 23. As noted above, theadditional current density is preferably provided by additional numbersof wire layers in the first and third coil segments 21, 23.

Preferably, the first and third coil segments 21, 23 are configured witha predetermined number of wire layers that extend about a first andthird solenoid longitudinal distance. The second segment 22 isconfigured with about half of the number of wire layers relative to thefirst and third coil segments 21, 23 and extends about a longer secondsolenoid longitudinal distance. Also, as illustrated in FIG. 3A,preferably the first and third coil segments 21, 23 include about fourwire wrap layers (wire is wrapped in four layers in these segments, onelayer on top of the other), each having about a 2.0 inch length, whilethe second segment 22 includes about two wire wrap layers having about a7.0 inch length. The solenoid 20 preferably is sized to provide about a6.0 inch inner diameter. These dimensions are particularly suitable fora single dose quantity of hyperpolarized gas that is held in a 3 inchdiameter spherical gas chamber 30 having a capillary stem 35 as shown inFIG. 1. This gas chamber 30 and solenoid 20 configuration provides abouta 1.5 inch radial separation between the solenoid inner diameter and thegas chamber outer diameter. Of course, other solenoid 20 dimensions andcoil segment configurations (lengths, numbers of layers etc., and/orpermanent magnet arrangements) can be used for alternatively sized andshaped containers 30.

In its preferred operative position, as shown in FIGS. 1 and 2, the gaschamber 30 is preferably disposed in the solenoid 20 such that thespherical or major portion 33 of the gas chamber 30 is positioned thearea of increased homogeneity within the solenoid 20 (e.g., the centerof the solenoid 20 and/or the center of the second coil segment 22). Thepositioning can be secured by suspending the gas chamber 30 from the topplate 60A′ (FIG. 1) or by positioning a-non-conducting gas friendlyplatform or base or the like under the gas chamber 30 (not shown).Preferably, as shown in dotted line in FIG. 2, the gas chamber 30 isdisposed in the solenoid 20 such that it rests on hyperpolarized gasfriendly packaging which acts as vibration damping material 50 to helpinsulate the gas chamber 30 from undue exposure to vibration duringtransport. Also as shown, the packing material 50 extends securely andsnugly around and about the capillary stem 35 to help cushion andinsulate the container during shipment. In any event, it is preferredthat the gas chamber 30 be well supported in the high homogeneityregion, as the magnetic holding field's homogeneity is spatiallydetermined (spatially variable) and translation of the gas chamber 30thereabout can result in the hyperpolarized gas being potentiallyexposed to an inhomogeneous region, thereby potentially reducing thepolarized life of the hyperpolarized gas product.

In any event, it is preferred that the coil segment configuration issuch that each of the first and third coil segments 21, 23 provides anincreased current density relative to the second or intermediate coilsegment 22. In this configuration, the solenoid electrical coil segments21, 22, 23 are sized and configured with respect to the solenoid volumeto provide adequate magnetic field homogeneity over a larger centralvolume and advantageously do so in a relatively compact manner relativeto previous coil designs. Preferably, the three coils 21, 22, 23 areelectrically connected in series and, as such, the end coil segments areelectrically connected to the power source 40 (FIG. 1). Of course, thecurrent can alternatively be separately provided or otherwiseelectrically supplied to the coil segments 21, 22, 23. For example, aswill be appreciated by those of skill in the art, a separate battery andassociated circuitry (not shown) can supply the second coil 22 while afirst battery is used to power the first and third coils 21, 23.

In a preferred embodiment, the first and third coil segments have about198 windings while the second or central coil segment includes about 347windings (i.e., the second coil segment 22 preferably has above about1.5 times the number of windings of the first and third coil segments21, 23). Thus, in a preferred embodiment, the solenoid 20 is configuredwith about 743 windings thereon. For this configuration the ratio offield strength to current is about 23.059 G/A. Thus, the field strengthat 300 mA is about 6.918 gauss and the field strength at 320 mA is about7.379 gauss. A suitable wire is 18 gauge HML from MWS Wire Industries,Westlake Village, Calif.

Preferably, for transit purposes, the transport unit power source 40 isa 12V DC battery (such as those used to power motorcycles). However, atdocking stations or an end-use site, the transport unit 10 can beconveniently plugged into an exterior power source to bypass andpreserve the battery charge. Also the transport unit power source 40 isconfigured via operating circuitry 50 to provide an adjustable currentsupply to the solenoid 20 of about 100 mA to about 2.0 A. Thus, thesolenoid 20 is preferably configured to provide a magnetic holding fieldof between about 2 to 40 gauss. The operating circuitry 50 of thetransport unit 10 will be discussed further below.

Gas Chamber

Preferably, the gas chamber 30 is configured to provide a quantity ofhyperpolarized gas which can be conveniently delivered to an end pointin a user-friendly single dose volume (but of course can also beconfigured to provide multiple or partial dose quantities) ofhyperpolarized gas. In a preferred embodiment, the gas chamber 30 is a100-200 cm³ gas spherical chamber. For ³He, it is preferred that the gaschamber 30 is pressurized to about 4-12 atmospheres of total pressure,and more preferably it is pressurized to about 5-11 atmospheres of totalpressure. Pressuring an appropriately sized gas chamber can allow thehyperpolarized gas to be released through the exit as the pressure actsto equalize with ambient conditions. Thus, by merely opening the valve32, the hyperpolarized gas can be directed to a patient or a patientdelivery system with minimal handling (and thus minimal potentiallydepolarizing interaction). Alternatively, as shown in FIGS. 12A, 12B,and 13 the hyperpolarized gas can be divided and diluted orappropriately sized either at a polarization site or at a second siteremote from the polarization site into several patient delivery sizedbags with expandable chambers for (further) transport and delivery. Thewalls of the expandable chamber bags can be depressed to expel the gasmixture held therein with a minimum of extraction equipment required.

It should be noted that for hyperpolarized ³He, at about 10 atm ofpressure, the theoretical T₁ due to interactions with otherhyperpolarized nuclei is about 75 hours. Substantially higher pressuresallow more gas product to be shipped in the container and reduces thesensitivity of the hyperpolarized gas to gradient relaxation, but thegas-gas collision relaxation can become more prevalent. In contrast, for¹²⁹Xe, it is preferred that the gas pressure be about 10 atm or less,because higher pressures can dramatically reduce the expected relaxationtime of the hyperpolarized ¹²⁹Xe (i e., at 10 atm, the T₁ is 5.6 hours).

In a preferred embodiment of the instant invention, as shown in FIG. 4,the gas chamber 30 includes a capillary stem 35 which is sized andconfigured to minimize the travel of hyperpolarized gas atoms out of thespherical volume and acts to keep most of the hyperpolarized gas awayfrom the valve 32. More specifically, the capillary is dimensioned suchthat the ratio of the main body volume to the capillary volume,multiplied by the diffusion time of ³He (at fill pressure) to go twicethe length of the capillary, is greater than the desired T₁. As such, amajor portion of the hyperpolarized gas remains in the region of highesthomogeneity within the solenoid 20 where it is best protected fromdepolarizing effects during transport. Preferably, the capillary stem 35includes about a 1.0 mm inside diameter and has a length, which issufficient to allow proper positioning of the sphere within the regionof homogeneity in the solenoid 20. In the preferred embodiment of thesolenoid 20 described above, the capillary stem 35 is approximately 4inches long. As such, for a gas chamber 30 with a three inch diametersphere, the capillary stem 35 is preferably longer than the than thesphere holding (body) portion 33 of the gas chamber 30. Also preferably,the inner diameter of the capillary stem 35 is sufficiently small as toslow movement of the hyperpolarized atoms relative to the valve 32,thereby keeping a substantial portion of the hyperpolarized gas in thespherical volume 33 and thus within the high-homogeneous field region.

As also discussed above, even if the transport unit 10 shields orprotects the hyperpolarized gas from EMI and static magnetic fieldgradients, the surface relaxation rate associated with the container,the valve(s), and other hyperpolarized gas contacting components candeleteriously affect the polarization lifetime of the hyperpolarizedgas. As such, particularly for hyperpolarized ³He, and for multi-dosecontainers 30L (FIG. 12A, 13) it is preferred that the gas chamber 30primarily comprise an aluminosilicate material. Aluminosilicatematerials have been shown to have long surface relaxation times. The gaschamber 30 may be manufactured from GE180™, although, of course, otheraluminosilicates may be used. Typically a transition glass is used toattach the borosilicate (Pyrex® valve 32 of the aluminosilicate gaschamber 30. Suitable valves 32 for use in the gas chambers 30 is partnumber 826460-0004 which is available from Kimble Kontes, located inVineland, N.J. The valves 32 can be further modified to coat or replaceany paramagnetic or ferromagnetic impurities, or may be treated orconditioned to remove or minimize the amount of impure or depolarizingmaterials that are positioned proximate to the hyperpolarized gas.Suitable transition glass includes uranium glass.

Alternatively, other polarization-friendly materials can be used, suchas high purity metals or polymers with metallized surfaces, polymers andthe like. “High purity” as used herein means materials that aresubstantially free of paramagnetic or ferrous materials. Preferably, themetallic materials include less than 1 part per million paramagnetic orferrous impurities (such as iron, nickel, chromium, cobalt and thelike). In an alternate preferred embodiment, as shown in FIGS. 12A and13, the gas chamber can be a resilient bag 30 b such as a single ormultiple polymer layer bag having a metallic film layer or inner surfaceor surface layer which is formed from one or a combination of a highpurity metal such as gold, aluminum, indium, zinc, tin, copper, bismuth,silver, niobium, and oxides thereof. Additional descriptions ofpreferred hyperpolarization materials and containers, O-rings and thelike are included in co-pending U.S. patent application Ser. No.09/126,448 entitled “Containers for Hyperpolarized Gases and AssociatedMethods” (and its related application) as discussed under theSurface-induced Relaxation section hereinabove. The resilient bag 30 bmay include a capillary stem (not shown) and/or a fluid port isolationmeans to inhibit the hyperpolarizedi gas from contacting potentiallydepolarizing valves and fittings during transport or storage.

It is also preferred that the gas chamber 30 be configured as a spherebecause it has a geometry that minimizes the surface area/volume ratioand thus the surface-induced contact relaxation. Further, since thesolenoid 20 described above generates a region of high homogeneity thatis typically generally spherical in shape, making the gas chamberspherical in shape maximizes the volume of the gas chamber that fits thehomogeneous region.

In another preferred embodiment, the transport unit 10 is configured inat least two different sizes, a first size for transporting largequantities of gas in a single container, and a second size fortransporting one or more (preferably a plurality of single-sizeddosages) for facilitating distribution of single-use doses ofhyperpolarized substances or formulations at remote sites to retainsufficient polarization to allow clinical useful images over longertransport distances and elapsed times from original the original pointof polarization. FIGS. 12A, and 13 illustrate a multi-bolus or dosecontainer 30L (i.e., a relatively large capacity container) and aplurality of smaller resilient bag 30 b containers (i.e., bags withexpandable chambers). The bag container 30 b may include a capillarystem similar to that used for the rigid container 30 discussed above(not shown). Similar, to the gas chamber 30, the NMR coil 75 can bepositioned on an outer surface thereof to monitor polarization duringtransport. Further details regarding preferred bag materials andconfigurations are discussed in co-pending and co-assigned U.S. PatentApplication entitled, “Resilient Containers for Hyperpolarized Gases andAssociated Methods,” identified by Attorney Docket No. 5770-12IP andrelated U. S. patent application Ser. No. 09/126,448, incorporated byreference herein.

The multi-bolus container 30L is used to dispense desired formulations,concentrations, and/or mixtures of the hyperpolarized gas (with orwithout other substances, liquids, gases (such as nitrogen), or solids)at a remote site. The multi-dose container 30L may be the polarizationchamber or optical cell itself. The magnetic field generator ispreferably a correspondingly sized solenoid 20, but can also be providedby permanent field magnets (not shown). Of course, a single sizedtransport unit (or even the same transport unit) can be used totransport the hyperpolarized gas to the second and third sites, i.e.,the second transport unit 10 s may be sized and configured the same asthe first transport unit 10 f as needed. Alternatively, the firsttransport unit may be larger than the second or the second may be largerthan the first depending on how the hyperpolarized gas is distributedand the shape and size and number of the second containers positionedfor transport from the second site.

FIG. 13 illustrates that the resilient bags 30 b can each have anindividual magnetic field generator shown as a solenoid 20 operativelyassociated therewith. FIG. 12A illustrates one alternate configurationwith a single magnetic field generator (also shown as a solenoid 20)sized and configured to hold a plurality of bags 30 b therein. As shownin FIG. 12B, a tray 630 can be used to hold a plurality ofhyperpolarized substance filled bags and translated into the solenoid20′ to position them in the desired region within the solenoid foreffective shielding as discussed above. The tray 630 can also facilitateremoval at a delivery site. Preferably, the tray is formed ofnon-conductive polarization friendly materials. Of course, the tray 630can be alternatively configured such as with compartments and slidingand locking means which ratchet or lock for positionally affirmativelylocating the bags, as well as a handle or extension means to allowcentral or recessed positioning of the tray and bags within the desiredregion of homogeneity.

Operating Circuitry

Preferably, the transport unit 10 includes operating circuitry 50 thatis operably associated with the solenoid 20 and the power source 40.Preferably, the internal power source 40 is a battery as describedabove, but can also be operably associated with an external power sourcevia an external power connection 141 (FIG. 5). As shown schematically inFIG. 8, the operating circuitry 50 preferably includes a powermonitoring switching circuit 125. As shown in FIG. 7, the powermonitoring and switching circuit 125 includes a relay switch 145, acurrent monitor 150 and an on/off switch output 160 which is connectedto the input of the current load into the solenoid 20. Advantageously,the power monitoring circuitry 125 is preferably configured toautomatically switch between the different power sources (40, 140)without interruption of the current to either the operating circuitry 50or the solenoid 20. Preferably, the power monitoring switching circuit125 manages the power supply such that the transport unit 10 is poweredfrom the internal power source 40 (battery) only when needed. Forexample, when the transport unit 10 is not easily connected to anexternal power source 140, the power monitoring circuit 125 engages thebattery 40 to supply the power to the transport unit 10. Preferably, thepower monitoring circuit 125 then disengages the battery 40 when thetransport unit 10 is connected to a viable external power source 140(such as a wall or vehicle power outlet) when the external connectorport 141 is connected to the external source 140. In a preferredembodiment, as shown in FIG. 7, the power monitoring circuit 125 isoperably associated with recharging circuit 148 which allows theinternal battery 40 to be recharged when the transporter is powered froman external supply 140.

Of course, the operating circuit 50 can also include other componentsand circuits such as a battery monitor 171 (FIG. 5) and an audible andor visual alarm (not shown) to indicate when the battery 40 is low.Preferably, as also shown in FIGS. 5 and 8, the transport unit 10includes a current readout 151 associated with the power monitoringcircuit 125. As shown, the current readout is a LCD display 151, whichwill allow a custodian to visually affirm that the transport unit isfunctioning properly and enable him to monitor the current runningthrough the solenoid. Also as shown in FIG. 8, the operating circuitry50 preferably includes a current adjustment means 180 for increasing ordecreasing the current delivered to the solenoid 20. In a preferredembodiment, the current adjustment means 180 is a rheostat operated bythe current control knob 180 (FIG. 5). As discussed above, theadjustable current means preferably is adjustable to supply betweenabout 100 mA to about 2.0 A.

The current adjustment allows the operating circuitry 50 to adjust thecurrent in response to the needs of the transport unit 10. For example,the current can be adjusted to provide a custom holding fieldcorresponding to the type of hyperpolarized gas being transported.Additionally, the current to the solenoid 20 can be adjusted tocompensate for electronic or mechanical system variation (i.e., batterydrainage, electronic drift, coil resistance variability due totemperature), thereby maintaining the desired holding field strength.The operating circuit preferably includes a means for adjusting themagnetic field strength of the magnetic holding field, which preferablyoperates to shift the Larmor frequency of the spins associated with thehyperpolarized gas. Such magnetic field adjustability is useful forperforming of NMR measurements, or to avoid electromagnetic interferenceat a particular frequency or frequency range. The NMR measurement systemwill be discussed further below.

As with all materials that contact, or are positioned near or proximateto the hyperpolarized gas, it is preferred that the operating circuitry50 contain minimal magnetically active materials and components such asiron transformers. However, if such materials or components are used,then it is preferred that they be positioned a sufficient distance fromthe gas chamber 30 and the solenoid 20 so that they do not cause unduegradient relaxation. Further, it is preferred that temperature sensitivecomponents be removed from the operating circuit 50 in order to providea reliable, consistent circuit which can tolerate broad temperatureranges (inside and outside). Of course the operating circuitry 50 may bepresent in hardware, software, or a combination of software andhardware.

Portable Monitoring (NMR Coil/Polarimetry)

Preferably, the transport unit 10 is operably associated with apolarization monitoring system that is configured to monitor thepolarization level of the hyperpolarized gas in the gas chamber 30.Advantageously, such system can be used in transit or at a desiredevaluation site. For example, prior to release of the gas from thetransport unit 10, the monitoring system can acquire a signalcorresponding to the polarization level of the hyperpolarized gas in thetransport unit 10 and thus indicate the viability of the gas prior todelivery or at a receiving station at the point of use. This can confirm(reliably “inspect”) the product and assure that the product meetspurchase specification prior to acceptance at the use site.

The polarization monitoring system can also be used with the transportunit 10 to evaluate magnetic holding field fluctuations duringtransport. Further, the monitoring system can automatically adjust thecurrent to compensate for detected fluctuations. Additional details of asuitable monitoring systems and methods for implementing same arediscussed in co-pending and co-assigned U.S. patent application,entitled “Portable Hyperpolarized Gas Monitoring System, ComputerProgram Products, and Related Methods,” identified by Attorney DocketNo. 5770-17. The contents of this application are hereby incorporated byreference as if recited in fall herein.

As shown in FIG. 1, the transport unit 10 preferably includes a NMRtransmit/receive coil 75, which is positioned such that it (securely orfirmly) contacts the external wall of the storage chamber 30. The NMRcoil 75 includes an input/output line 375 that is operably associatedwith a NMR polarimetry circuit and a computer (typically an externalportable computer device 500, as shown in FIG. 5). Preferably, thetransport unit 10 includes a computer access port 300 which is operablyassociated with the operating circuitry 50 and the NMR coil 75 via thecoaxial BNC bulkhead 275. The NMR coil 75 can be used with themonitoring system to evaluate the polarization level of thehyperpolarized gas in a substantially nondestructive evaluationtechnique.

Alternatively, or in addition to the (portable) monitoring system, thetransport unit 10 is preferably configured to conveniently dock into a(remote) site calibration station 500, as shown in FIG. 9. Generallydescribed, as shown in FIG. 9, the polarization detection can be carriedout at a calibration station 500 which preferably uses a low-field NMRspectrometer to transmit RF pulses to surface coils 75 positionedproximate to the hyperpolarized gas sample. The spectrometer thenreceives at least one signal back from the NMR coil 75 corresponding tothe hyperpolarized gas. The signal is processed and displayed 565 todetermine the polarization level of the hyperpolarized gas (preferablythis reading is taken while the gas is contained in the gas chamber 30within the transport unit 10).

As shown, the calibration station 500 preferably includes a set ofHelmholtz coils 552 (preferably of about 24 inches in diameter) toprovide the low magnetic field and another external NMR surface coil(not shown). The additional NMR surface coil is preferably sized andconfigured at about 1 inch in diameter and with about 350 turns. The NMRsurface coil is configured to be received into a non-metallic platform170 and is arranged to be substantially flush with the upper surface ofthe platform to be able to contact the patient delivery vessel 575.Also, the NMR coil is preferably positioned in the center of theHelmholtz coils 552. The term “low field” as used herein includes amagnetic field under about 100 Gauss. Preferably, the calibrationstation 500 is configured with a field strength of about 5-40 Gauss, andmore preferably a field strength of about 20 Gauss. Accordingly, thecorresponding ³He signal frequency range is about 16 kHz-128 kHz, with apreferred frequency of about 64 kHz. Similarly, the ¹²⁹Xe signalfrequency range is about 5.9 kHz-47 kHz, with a preferred signalfrequency of about 24 kHz.

Preferably, the hyperpolarized gas is contained in a patient deliverybag container 30 b which is positioned on the top surface of the surfacecoil (not shown) and substantially in the center of the Helmholtz coils552. Generally described, in operation, a selected RF pulse (ofpredetermined frequency, amplitude, and duration) is transmitted fromthe NMR device 501 to the surface coil (not shown). Alternatively, thecalibration station 500 can be used to transmit the selected RF pulseinside the transport unit 10 via connection 553. In any event, the RFpulse frequency corresponds to the field strength of the magnetic fieldand the particular gas, examples of which are noted above. This RF pulsegenerates an oscillating magnetic field which misaligns a small fractionof the hyperpolarized ³He or ¹²⁹Xe nuclei from their static magneticfield alignment. The misaligned nuclei start precessing at theirassociated Larmour frequency (corresponding to pulse frequency). Theprecessing spins induce a voltage in the surface coil that can beprocessed to represent a signal 565. The voltage is received back(typically amplified) at the computer and the signal fits anexponentially decaying sinusoid pattern. (As shown, the displayed signal565 is the Fourier transform of the received signal). The initialpeak-to-peak voltage of this signal is directly proportional topolarization (using a known calibration constant). The computer 500′ canthen calculate the polarization level and generate calculated preferreduse dates and times associated with desired polarization levels. As willbe recognized by those of skill in the art, other calibration orhyperpolarization level determination methods can also be employed andstill be within the product identification and calibration orproduct-use or expiration determination methods contemplated by thepresent invention. For example, by detecting the minute magnetic fieldgenerated by the polarized ³He spins, one can determine a polarizationlevel associated therewith.

In an alternate embodiment, the transport units 10″, 10′″ comprise aplurality of gas chambers 30 (FIGS. 6, 6A) or 30 b (FIG. 12A and 13) andeach gas chamber 30 preferably includes an individual NMR coil 75 whichis positioned adjacent each gas chamber within the solenoids of thetransport unit 10″, 10′″. It is further preferred that each gas chamber30 be substantially electrically isolated from the other gas chambers 30such that each gas chamber 30 is individually monitorable (individuallyexcitable) for hyperpolarization level and each is individually tunable(adjustable field strength and coil current). In another alternateembodiment, as shown in FIG. 6B, the transport unit 10″″ can beconfigured with a single coil 20′ which is sized and configured tosurround a plurality of gas chambers 30 therein (see also FIG. 12A).When positioning the containers 30 within the transport units (if thecontainers have necks or capillary stems, whether for single or multiplegas container units), neck or stem orientation can be oriented indifferent directions. Further, although the transport units shown inFIGS. 6, 6A, and 6B illustrate side by side gas containers, the presentinvention is not limited thereto. For example, the transport unit can beconfigured to comprise a plurality of units that are stackedlongitudinally with capillary stems extending in the same or opposingdirections. FIG. 12A illustrates one example, a plurality of bags 30 bpositioned in substantial linear alignment (whether longitudinal orlateral). An NMR coil 75 can also be attached to each bag 30 b held fortransport or storage (not shown).

Advantageously, a transport unit comprising a solenoid 20 hassuccessfully supported a T₁ of ³He of 45 hours (valved gas chamber)while an unvalved model (sealed) gas chamber (pressurized to about 2.2atm, not shown) has supported a T₁ of 120 hours. These exemplary T₁'swere for ³He polarized at a production site and transported in thetransport unit 10 for a travel time of about 30 hours (approximately 28hours where the unit was physically removed from its “home-base” orpolarizer) and where the unit was actually in transit for approximately10 hours. The gas chambers 30 in the transport unit 10 were exposed toenvironmental conditions while traveling to a use site in a vehicle.

Central Production Site; Remote Use Site

Use of a remote polarization production site typically requires longerT₁'s relative to an on-site polarization apparatus to allow adequateshipping and transport times. However, a centrally stationed polarizercan reduce equipment and maintenance costs associated with a pluralityof on-site units positioned at each imaging site and the transport unitsof the instant invention can allow increased transport times with longerT₁ times over those conventionally achieved. In a preferred embodiment,a production polarizer unit (not shown) generates the polarized gas aproduction site. The gas chamber 30 (or 30 b) is in fluid communicationwith the polarizer unit such that the polarizer unit produces anddirects the polarized gas to the gas chamber 30. Preferably, the gaschamber 30 is held in the transport unit enclosure 65 (FIG. 1) (orindividual enclosure 65A-D, FIGS. 6, 6A, and 6B) during the fillingstep. More preferably, the container is positioned in the transport unitwithin the homogeneous holding field therein prior to the filling step.After a sufficient quantity of hyperpolarized gas is captured in the gaschamber 30, the valve 32 is then closed (the gas chamber is sealed).Thus, the solenoid 20 in the transport unit 10 is activated (preferablyprior to the filling step, but can also be activated after the containeris sealed, if the container is otherwise protected such as on-board thepolarizer unit during fill. In operation, the power switch 161 (FIG. 5)on the transport unit 10 is turned to the “on” position and electricalcurrent is supplied to the solenoid 20 such that about a 7 Gaussmagnetic holding field is generated as discussed above. Thehyperpolarized gas is shielded from stray magnetic gradients within thetransport unit 10 until and after delivery to a remotely located site.When desired, the hyperpolarized gas can be directed or released fromthe gas chamber 30 and dispensed to a patient via some patient deliverysystem (temporally limited to its end use time) such that thehyperpolarized state of the gas at delivery is sufficient to produceuseful clinical images.

Another aspect of the present invention is a system for distributinghyperpolarized gas products such that single use or patient sized dosesof hyperpolarized gases have increased shelf life or useful polarizationlife. The system includes a first transport unit 10 f (schematicallyshown by dotted line box in FIG. 12A) which is sized and configured tohold at least one multi-dose container 30L therein. The system alsoincludes at least one second transport unit 10 s (schematically shown inFIG. 12A)sized mad configured to carry a plurality of single dosecontainers (such as for example shown by 30 or 30 b in FIGS. 6A, 6B, and12A, 13, respectively) therein. Preferably, the multi-dose container isa rigid body container 30L and the single dose containers are resilientcontainers 30 b having expandable chambers to allow easy delivery oradministration at a use site as described above. In a preferreddistribution system, the hyperpolarized gas is collected in amulti-bolus container (such as that shown as container 30L in FIGS. 12A,12B, and 13) at the polarization site and transported in a suitablysized transport unit 10 f to a second site remote from the first site.This multi-bolus container 30L can be the optical cell itself, or othersuitable container configuration such as those discussed above.

In one embodiment, as shown in FIG. 12A, the multi-dose container 30L istransported to a pharmaceutical distribution point where thehyperpolarized gas in the multi-dose container 30L can be dispensed orformulated into the proper dosage or mixture according to standardpharmacy or drug manufacturer operation. For example, but not limitedto, this dispensing or formulation activity may include solubilizing thegas in a carrier liquid, adjusting the concentration, preparing themixture for injection or inhalation or other administration as specifiedby a regulatory agency directive or physician, or combining one or moredifferent gases or liquids or other substances with the transportedhyperpolarized gas. Preferably, the materials used to form the productare suitable for administration to an in vivo subject (pharmaceuticalgrade substance). In any event, at the second site, the hyperpolarizedgas held in the multi-bolus container 30L is preferably dispensed intosingle use, application-sized, or prescripted amounts or doses ofhyperpolarized product into proportionately sized resilient containers30 b. Proper conditioning of the bag containers 30 b is preferablyobserved as will be discussed further below.

Subsequent to the dispensing step, the second or subsequent (preferably)single-use sized container can be delivered to a proximately located usesite (if the second site is proximate or part of a clinical use sitesuch as a hospital). Alternatively, at the second site, at least one bag30 b is positioned in a second transport unit 10 which is suitably sizedand configured to hold the bag therein. Preferably, the transport unit10 s is configured to hold a plurality of bags as shown in FIGS. 12A,12B. In any event, one or more bags are positioned in a secondtransporting unit 10 s and delivered or transported to a third ortertiary site, preferably the clinical use site. Preferably, for bagcontainers, the transport unit 10 s includes a magnetic field generatorwith a region of high homogeneity. Preferably, the high homogeneity issuch that the gradients are less than about 10⁻³ cm⁻¹ over the volumeoccupied by the bags 30 b.

In a preferred embodiment, the first transport distance is such that thehyperpolarized gas is moved at increased times or distances overconventional uses. Preferably, the transport units and associatedcontainer of the present invention are configured such that duringtransport and/or storage, the hyperpolarized gas (particularly ³He)retains sufficient polarization after about at least 10 hours frompolarization, and more preferably after about at least 14 hours, andeven more preferably greater than about 30 hours after polarization andwhen transported to a second site (and even then a third or tertiarysite). Further, the transport unit and associated containers arepreferably configured to allow greater transit distances or times fromthe original polarization point in a manner in which the hyperpolarizedproduct retains sufficient polarization to provide clinically usefulimages. This distribution system is in contrast to the conventionalprocedure, whereby the hyperpolarized gas is produced at a polarizationsite and rushed to a use site (which is typically relatively close tothe polarization site).

Preconditioning the Container

Preferably, due to susceptibility of the hyperpolarized gas toparamagnetic oxygen as noted above, the gas chamber 30 is preconditionedto remove contaminants. That is, it is processed to reduce or remove theparamagnetic gases such as oxygen from within the chamber and containerwalls. For containers made with rigid substrates, such as Pyrex™, UHVvacuum pumps can be connected to the container to extract the oxygen.Alternatively, for rigid and/or resilient containers (such as polymerbag containers), a roughing pump can be used which is typically cheaperand easier than the UHV vacuum pump based process. Preferably, forresilient bag containers, the bag is processed with several purge/pumpcycles. Preferably this is accomplished by pumping at or below 40 mtorrfor one minute, and then directing clean (UHP) buffer gas (such asnitrogen) into the container at a pressure of about one atmosphere oruntil the bag is substantially inflated. The oxygen partial pressure isthen reduced in the container. This can be done with a vacuum but it ispreferred that it be done with nitrogen. Once the oxygen realizes thepartial pressure imbalance across the container walls, it will outgas tore-establish equilibrium. Typical oxygen solubilities are on the orderof 0.01-0.05; thus, 95-99% of the oxygen trapped in the walls willtransition to a gas phase. Prior to use, the container is evacuated,thus harmlessly removing the gaseous oxygen. Unlike conventional rigidcontainers, polymer bag containers can continue to outgas (trapped gasescan migrate therein because of pressure differentials between the outersurface and the inner surface) even after the initial purge/pump cycles.Thus, care should be taken to minimize this behavior, especially whenthe final filling is not temporally performed with the preconditioningof the container. Preferably, a quantity of clean (UHP or Grade 5nitrogen) filler gas is directed into the bag (to substantially equalizethe pressure between the chamber and ambient conditions) and sealed forstorage in order to minimize the amount of further outgassing that mayoccur when the bag is stored and exposed to ambient conditions. Thisshould substantially stabilize or minimize any further outgassing of thepolymer or container wall materials. In any event, the filler gas ispreferably removed (evacuated) prior to final filling with thehyperpolarized gas. Advantageously, the container of the instantinvention can be economically reprocessed (purged, cleaned, etc.) andreused to ship additional quantities of hyperpolarized gases.

It is also preferred that the container or bag be sterilized prior tointroducing the hyperpolarized product therein. As used herein, the term“sterilized” includes cleaning containers and contact surfaces such thatthe container is sufficiently clean to inhibit contamination of theproduct so that it is suitable for medical and medicinal purposes. Inthis way, the sterilized container allows for a substantially sterileand non-toxic hyperpolarized product to be delivered for in vivointroduction into the patient. Suitable sterilization and cleaningmethods are well known to those of skill in the art.

Hyperpolarized Gas Transport Protection System Examples

FIG. 11 illustrates a preferred system for protecting hyperpolarized(noble) gases (and hyperpolarized gas products in whatever form such asfluids, liquids, solids, and the like including other gas or liquidcomponents in whatever form as noted earlier). A quantity ofhyperpolarized gas product is introduced into a sealable containercomprising a gas chamber (and preferably a capillary stem) at aproduction site (Block 800). A quantity of a hyperpolarized gas iscaptured in the gas chamber (Block 810). A magnetic holding field isgenerated from a portable transport unit thereby defining asubstantially homogeneous magnetic holding field region (Block 820). Thegas chamber is positioned within the homogeneous holding region (Block830). Preferably, (as indicated by dotted line) the gas chamber ispositioned in the magnetic field holding region prior to filling. Thehyperpolarized gas product is shielded from stray magnetic fields tominimize the depolarizing effects attributed thereto such that thehyperpolarized gas retains a clinically useful polarization level at anend use site remote from the production site (Block 840). Preferably,the magnetic holding field step is provided by electrically activating alongitudinally extending solenoid positioned in the transport unit. Thesolenoid comprises a plurality of spatially separated coil segments(Block 821). It is also preferred that the shielding step be performedby shifting the resonance frequency of the hyperpolarized gas in thecontainer to a predetermined frequency as discussed above (Block 841).

FIG. 14 illustrates a method and/or system for distributinghyperpolarized gas products. Noble gas is polarized at a polarizationsite (Block 900). A quantity of hyperpolarized gas sufficient to providemultiple doses of hyperpolarized noble gas products are captured in amulti-dose container (Block 910). The multi-dose container is positionedin a portable transport unit which is configured to provide ahomogeneous magnetic field for holding a major portion of the multi-dosecontainer therein (Block 920). The multi-dose container in the transportunit is transported to a second site remote from the first orpolarization site (Block 930). At the second site, the hyperpolarizedgas in the multi-dose container is distributed into multiple separatesecond containers (preferably reduced or patient sized dose containers),and more preferably single dose bags (Block 940).

Preferably, at the second site, and also preferably prior to thedistribution step (Block 940), the multi-doses of gas are subdivided(Block 941) and processed into at least one desired formulation to forma hyperpolarized pharmaceutical grade product suitable for in vivoadministration (Block 942). Preferably, the processing and subdividingsteps are performed prior to the distribution of the gas into thesecondary containers for transport. Thus, the processing and/ordistribution step at the second site can include the steps offormulating or otherwise processing the hyperpolarized gas into asterile or non-toxic product such that it is suitable for in vivo humanadministration. The processing can include diluting concentration suchas by adding other inert gases (such as substantially pure, at leastgrade 5, nitrogen), or carrier or other liquids or substances. Theprocessing can include manipulating the hyperpolarized gas from themulti-dose container such that it is formulated into the proper dosageor mixture according to standard pharmaceutical industry operation. Thismay include solubilizing the gas, adjusting the concentration, preparingthe mixture for injection or inhalation or other administration asspecified by a physician, or combining one or more different gases orliquids or other substances with the transported hyperpolarized gas.Then, the formulated hyperpolarized product, substance, or mixture ispreferably dispensed into at least one second container, and preferablyinto a plurality of preferably single use size resilient containerswhich can be transported to a third or tertiary site.

From the second site, at least one of the second containers (preferablya single dose bag container) can be used to deliver a hyperpolarizedproduct to a user proximate to the second site (Block 970) or positionedwithin a second transport unit with a region of homogeneity (Block 950)and transported to a third site (preferably an imaging site) remote fromthe second site (Block 955). The delivery of the product at a siteproximate to the second site is especially applicable fordistribution-oriented second sites which are clinics (such as a wing ofthe hospital). The hyperpolarized product can then be administered to apatient at the imaging site or stored for futures use (Block 975). Theadministered hyperpolarized product is useful for obtaining clinicaldata associated with Magnetic Resonance Imaging and Spectroscopyprocedures. The transport units according to the present invention areconfigured such that during transport and/or storage the gas has propershielding as described herein.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. Although a few exemplary embodiments ofthis invention have been described, those skilled in the art willreadily appreciate that many modifications are possible in the exemplaryembodiments without materially departing from the novel teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of this invention as defined inthe claims. In the claims, means-plus-function clauses are intended tocover the structures described herein as performing the recited functionand not only structural equivalents but also equivalent structures.Therefore, it is to be understood that the foregoing is illustrative ofthe present invention and is not to be construed as limited to thespecific embodiments disclosed, and that modifications to the disclosedembodiments, as well as other embodiments, are intended to be includedwithin the scope of the appended claims. The invention is defined by thefollowing claims, with equivalents of the claims to be included therein.

That which is claimed is:
 1. A transport unit for transportinghyperpolarized gas products therein, said transport unit comprising: atleast one gas chamber configured to hold a quantity of hyperpolarizedgas product therein; and an electromagnet disposed in said transportunit, said electromagnet configured and sized to define a magneticholding field having at least one region of homogeneity therein, whereina major portion of each of said at least one gas chamber is sized andconfigured to reside in said magnetic field homogeneous region.
 2. Atransport unit according to claim 1, further comprising at least oneelectrical current carrying wire, wherein said at least one electricalwire is configured to generate at least a portion of said magneticholding field.
 3. A transport unit according to claim 1, wherein saidelectromagnet comprises at least one cylindrical solenoid.
 4. Atransport unit according to claim 3, wherein said at least one solenoidand gas chamber is a plurality of corresponding solenoids and gaschambers for transporting multiple doses of hyperpolarized gas productstherein.
 5. A transport unit according to claim 3, wherein said at leastone gas chamber is a plurality of separate gas chambers.
 6. A transportunit according to claim 3, wherein said solenoid comprises a pluralityof coil segments thereon.
 7. A transport unit according to claim 6,wherein said operating circuitry is configured to allow an adjustableamount of current to said solenoid thereby providing an adjustablemagnetic holding field strength.
 8. A transport unit according to claim6, wherein said plurality of coil segments includes spatially separatedfirst, second, and third coil segments.
 9. A transport unit according toclaim 3, said transport unit further comprising a metallic enclosure,wherein said solenoid is positioned in said enclosure such that itextends longitudinally therein.
 10. A transport unit according to claim9, wherein said enclosure includes at least one layer of an electricallyconducting metal thereon, thereby providing one or more of shieldingfrom external electromagnetic radiation and structural support duringtransport.
 11. A transport unit according to claim 3, wherein saidsolenoid provides a homogeneous magnetic holding field volume definedrelative to the center of said solenoid, and wherein said container hasa hyperpolarized product holding chamber configured and sized such thatsaid holding chamber is held in said homogeneous field volume.
 12. Atransport unit according to claim 9, wherein said enclosure includes atleast one layer of magnetically permeable material to provide at leastone of additional electromagnetic shielding, DC magnetic shielding, or aflux return.
 13. A transport unit according to claim 3, furthercomprising operating circuitry operably associated with said transportunit, said operating circuitry including a direct current power supplyoperably associated with said solenoid.
 14. A transport unit accordingto claim 13, wherein said operating circuitry is configured to directelectrical current to said solenoid to define the magnetic holding fieldhaving a field strength corresponding to the amount of current directedto said solenoid.
 15. A transport unit according to claim 10, whereinsaid solenoid is disposed in said transport unit such that itlongitudinally extends in said enclosure and defines a magnetic holdingfield which is substantially aligned with the earth's magnetic field.16. A transport unit according to claim 8, wherein said second coilsegment is disposed intermediate said first and third coil segments, andwherein said second coil segment has a lower number of electricalwindings per unit length then said first and third coil segments.
 17. Atransport unit according to claim 16, wherein said first and third coilsegments extend a first longitudinal distance along said solenoid andsaid second coil segment extends a second longitudinal distance alongsaid solenoid, and wherein said second distance is greater than saidfirst and third distance.
 18. A transport unit according to claim 1,wherein said gas chamber includes a gas holding chamber having a majorbody portion with a first length and a capillary stem with a secondlength, said capillary stem is in fluid communication with said gasholding chamber and having a capillary length and a capillary diameter,wherein said capillary length is greater than said major body portionlength.
 19. A transport unit according to claim 1, wherein said gaschamber is defined by at least one resilient bag defining at least oneexpandable gas holding chamber.
 20. A transport unit according to claim19, wherein said at least one gas chamber is a plurality of gas chambersdefined by a plurality of resilient bags for transporting multipleseparate doses of hyperpolarized products therein.
 21. A transport unitaccording to claim 20, further comprising a tray for holding saidplurality of bags, said tray configured and sized to reside within saidmagnetic field generator.
 22. A system of extending the polarizationlifetime of hyperpolarized gas during transport, comprising the stepsof: introducing a quantity of hyperpolarized gas product into a sealablegas chamber at a production site; capturing a quantity of hyperpolarizedgas product in the gas chamber; generating a magnetic holding field froma portable transport unit, thereby defining a substantially homogeneousmagnetic holding region therein; positioning a major portion of the gaschamber within the homogeneous holding region; transporting the capturedhyperpolarized gas in the gas chamber; and shielding the hyperpolarizedgas product to minimize the depolarizing effects of external magneticfields during said transporting step such that the hyperpolarized gashas a clinically useful polarization level at a site remote from theproduction site.
 23. A hyperpolarized gas protection system according to22, wherein said transport unit comprises a metallic enclosure, andwherein said step of shielding is performed by positioning said gaschamber in the metallic enclosure and electrically activating a solenoiddisposed in the metallic enclosure.
 24. A hyperpolarized gas protectionsystem according to 22, wherein said shielding step comprises shiftingthe normal resonant frequency of the hyperpolarized gas outside apredetermined frequency range.
 25. A hyperpolarized gas protectionsystem according to 22, wherein the transport unit is configured to holda plurality of separate gas chambers therein.
 26. A method according to22, wherein the transporting step is performed by transporting the gaschamber to a second site remote from the production site.
 27. A methodaccording to claim 26, wherein the gas chamber is configured as amulti-dose container, and further comprising the step of distributingthe transported hyperpolarized gas in the multi-dose container at thesecond site into a plurality of single-dose containers to provide asuitable amount of hyperpolarized gas product therein.
 28. A methodaccording to claim 27, further comprising the steps of transporting saidplurality of said single dose containers to a third site remote from thesecond site; administering the hyperpolarized product held in at leastone of said single dose containers to a patient; and obtaining an MRimaging or spectroscopy signal associated with same.
 29. A method fordistributing hyperpolarized noble gas, comprising the steps of:polarizing noble gas at a polarization site; capturing a quantity ofpolarized gas in a multi-dose container, the quantity of hyperpolarizedgas being sufficient to provide a plurality of doses of a hyperpolarizedproduct; positioning the first multi-dose container within a portabletransport unit, the transport unit configured to provide a homogeneousmagnetic field proximate to a major portion of the multi-dose containerheld therein; transporting the transport unit with the multi-dosecontainer to a second site remote from the polarization site; anddistributing the hyperpolarized gas held in the multi-dose containerinto multiple separate second containers at the second site.
 30. Amethod according to claim 29, wherein said transporting step comprisesshielding said hyperpolarized gas by activating an electromagnet in saidportable transport unit.
 31. A method according to claim 29, furthercomprising the steps of sub-dividing the hyperpolarized gas in the firstmulti-dose container at the second site; and processing the sub-dividedgas into at least one desired formulation to form a hyperpolarizedpharmaceutical product suitable for in vivo administration, theprocessing step being performed prior to said distributing step.
 32. Amethod according to claim 31, further comprising the steps of:positioning at least one of the multiple separate second containers withthe hyperpolarized gas product therein into a second transport unit, thesecond transport unit being configured to provide a region ofhomogeneity therefor; and transporting the second transport unit withthe at least one multiple separate second container to a third site. 33.A method according to claim 32, wherein at least one of the multipleseparate second containers comprises a patient dose sized resilient bag.34. A method according to claim 33, further comprising the steps of:administering said hyperpolarized pharmaceutical product in said secondcontainer to a patient; and obtaining clinically useful data associatedwith the administered hyperpolarized product via one or more of anMagnetic Resonance Imaging or Spectroscopy procedures.
 35. A methodaccording to claim 31, further comprising the steps of: positioning aplurality of patient-sized bags filled with the hyperpolarizedpharmaceutical product in said second transport unit; and transportingthe plurality of patient sized bags to a third site remote from thesecond site.
 36. A method according to claim 29, wherein thehyperpolarized gas comprises ³He, and wherein the multi-bolus containeris used to polarize a quantity of noble gas therein during saidpolarizing step at the polarization site.
 37. A portable transporter fortransporting or storing a quantity of hyperpolarized gas product,comprising: an enclosure having at least one wall with a skin depth of aconductive shielding material configured to provide a shield for aquantity of hyperpolarized gas from externally generated electromagneticinterference during transport from a polarization site to a use site,said enclosure defining a holding volume therebetween; at least onehyperpdlarized gas container positioned in said enclosure, said gascontainer having a major gas holding volume portion, and a magneticfield source positioned in said enclosure, said magnetic field sourceconfigured to provide a region of homogeneity proximate to saidhyperpolarized gas container; wherein the holding volume is sized andconfigured to hold said hyperpolarized gas container such that the majorvolume of said hyperpolarized gas container is spatially separated apredetermined distance from adjacent portions of said at least one wall,and wherein said predetermined distance is sufficient to increase theshielding effectiveness of said enclosure.
 38. A portable transporteraccording to claim 37, wherein said at least one wall comprises a pairof opposing longitudinally extending walls.
 39. A portable transportunit according to claim 37, wherein said magnetic field source is asolenoid.
 40. A portable transport unit according to claim 39, whereinsaid solenoid comprises a conductive material inner surface configuredto provide shielding.
 41. A portable transport unit according to claim37, wherein said predetermined separation distance is at least about 2.0inches.
 42. A portable transport unit according to claim 37, whereinsaid at least one gas container is a plurality of gas containers.
 43. Aportable transport unit according to claim 37, wherein said at least onegas container comprises a container which is also configured as anoptical pumping cell for the hyperpolarized gas held therein at apolarization site.
 44. A portable transport unit according to claim 37,wherein said predetermined separation distance provides a separationratio of less than about 0.60, the separation ratio being mathematicallyexpressed by the ratio of (a) the linear lateral half-width of the majorvolume portion of said gas container to (b) the linear minimumseparation distance of said at least one wall.
 45. A portable transportunit according to claim 37, wherein said magnetic field source is aplurality of electromagnetic field sources, at least one each for eachof said at least one containers held in said enclosure.
 46. A portabletransport unit according to claim 37, wherein said at least onecontainer comprises a capillary stem.